Comprehensive Physiology Wiley Online Library

Role of Mitochondrial DNA in Inflammatory Airway Diseases

Full Article on Wiley Online Library



Abstract

The mitochondrial genome is a small, circular, and highly conserved piece of DNA which encodes only 13 protein subunits yet is vital for electron transport in the mitochondrion and, therefore, vital for the existence of multicellular life on Earth. Despite this importance, mitochondrial DNA (mtDNA) is located in one of the least‐protected areas of the cell, exposing it to high concentrations of intracellular reactive oxygen species (ROS) and threat from exogenous substances and pathogens. Until recently, the quality control mechanisms which ensured the stability of the nuclear genome were thought to be minimal or nonexistent in the mitochondria, and the thousands of redundant copies of mtDNA in each cell were believed to be the primary mechanism of protecting these genes. However, a vast network of mechanisms has been discovered that repair mtDNA lesions, replace and recycle mitochondrial chromosomes, and conduct alternate RNA processing for previously undescribed mitochondrial proteins. New mtDNA/RNA‐dependent signaling pathways reveal a mostly undiscovered biochemical landscape in which the mitochondria interface with their host cells/organisms. As the myriad ways in which the function of the mitochondrial genome can affect human health have become increasingly apparent, the use of mitogenomic biomarkers (such as copy number and heteroplasmy) as toxicological endpoints has become more widely accepted. In this article, we examine several pathologies of human airway epithelium, including particle exposures, inflammatory diseases, and hyperoxia, and discuss the role of mitochondrial genotoxicity in the pathogenesis and/or exacerbation of these conditions. © 2021 American Physiological Society. Compr Physiol 11:1485‐1499, 2021.

Figure 1. Figure 1. Overview of mtDNA during oxidative lung injury. This schematic represents the progression from oxidative lung injury to mitogenomic damage to impairment of metabolic endpoints.
Figure 2. Figure 2. Illustration depicting three types of mitochondrial heteroplasmy at a single mtDNA locus. Homoplasmy (a), which is the absence of a minor allele, microheteroplasmy (b), which is the homeostatically maintained presence of low‐frequency minor alleles (generally less than 10%), and heteroplasmy (c), which is the presence of a biologically significant percentage of minor alleles.
Figure 3. Figure 3. Mitochondrial responses to oxidative lung injury and cellular stress. The mitochondrion is sensitive to a wide range of endogenous and exogenous stressors and reacts to these stimuli through a multitude of pathways. Mitochondrial responses provide several measurable markers of cellular stress which are potentially predictive of mitogenomic damage.


Figure 1. Overview of mtDNA during oxidative lung injury. This schematic represents the progression from oxidative lung injury to mitogenomic damage to impairment of metabolic endpoints.


Figure 2. Illustration depicting three types of mitochondrial heteroplasmy at a single mtDNA locus. Homoplasmy (a), which is the absence of a minor allele, microheteroplasmy (b), which is the homeostatically maintained presence of low‐frequency minor alleles (generally less than 10%), and heteroplasmy (c), which is the presence of a biologically significant percentage of minor alleles.


Figure 3. Mitochondrial responses to oxidative lung injury and cellular stress. The mitochondrion is sensitive to a wide range of endogenous and exogenous stressors and reacts to these stimuli through a multitude of pathways. Mitochondrial responses provide several measurable markers of cellular stress which are potentially predictive of mitogenomic damage.
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Ryan J. Snyder, Steven R. Kleeberger. Role of Mitochondrial DNA in Inflammatory Airway Diseases. Compr Physiol 2021, 11: 1485-1499. doi: 10.1002/cphy.c200010